Pour-on formulations are utilized by the animal industry as a means for administering certain anthelmintic agents and veterinary medicines to animals. In practice, the medicated formulation is applied directly to the external skin or hide of the animal. As such, some practitioners have extended the term pour-on to include formulations which may be dispersed in water and applied as aqueous dips, baths or sprays. In the present specification, however, the term xe2x80x9cpour-onxe2x80x9d is not intended to suggest this type of application. Rather, the formulation of this invention is a non-aqueous formulation which is applied with the assistance of a suitable device such as a measuring cup, a squirt bottle or an automatic microspray device which permits directed application of a small amount of formulation onto the skin of the animal being treated.
While a number of anthelmintic agents and veterinary medicines such as tetramisole, levamisole, trichlorphon and fenthion, have been successfully prepared as pour-on compositions, all veterinary medicines do not lend themselves to such formulation. Moreover, those medicines that have been so formulated generally have been found to be significantly less effective as pour-on formulations than they are when administered orally or parenterally.
Presently, the art appears to describe no pour-on formulations which do not wash off during rainfall or which retain efficacy on wet animals. From a practical standpoint, a product which lacks efficacy on wet skin or hide is extremely inconvenient to use due to the extra burden on the part of the farmer to keep the animals dry in order to effectively treat them with pour-on medicine.
For successful formulation as a pour-on, a drug must be active when dissolved, dispersed or emulsified in a suitable solvent which is well tolerated by the animals skin. The drug must be readily adsorbable through the animals skin and the composition as a whole should disperse or spread well over the animals body and be relatively non-viscous when so spread. It must also be recognized that each drug has its own chemical and physical properties that require special consideration and limit the types of solvents, diluents, stabilizing agents and other formulatory agents that can be employed in the formulation of that particular drug or medicine.
It is, therefore, an object of the present invention to provide a non-irritating pour-on formulation which is effective on dry or wet skin and hide for the control of insects and internal and external parasitic infections and infestations of farm and companion animals and which resists wash off during normal precipitation.
It is also an object of this invention to provide an effective non-aqueous pour-on formulation that contains, as the active ingredient, an antibiotic selected from LL-F28249xcex1, a 23-oxo or 23-imino derivative of LL-F28249xcex1-xcex, a milbemycin molecule or an avermectin molecule, which exhibits excellent penetration of the animals hide or skin, spreads well and rapidly over the animals body, is non-malodorous, non-irritating and relatively non-viscous toward dust, dirt and foreign matter encountered by the treated animals.
It is a further object of this invention to provide a method for treating, controlling, preventing or protecting quadruped farm and companion animals from infestation and infection by helminths, acarids and arthropod endo- and ectoparasitic insects by topically applying to said animals a pour-on formulation containing an anthelmintically, acaricidally or arthropod endo- or ectoparasiticidally effective amount of the antibiotic LL-F28249xcex1, LL-F28249xcex2 or a 23-oxo or 23-imino derivative of LL-F28249xcex1, such as 23-(O-methyloxime)-LL-F28249xcex1 or 23-(O-methyloxime)-LL-F28249xcex2.
The present invention relates to non-aqueous pour-on, water-fast compositions and the method of use thereof for treating, controlling, preventing and protecting homothermic animals, such as mammalian quadrupeds, from infestation and infection by internal and external parasites. More particularly, this invention relates to non-aqueous pour-on compositions containing as the active ingredient an anthelmintically, acaricidally or arthropod endo- or ectoparasiticidally effective amount of a compound selected from compounds designated LL-F28249xcex1-xcex, a 23-oxo or 23-imino derivative of LL-F28249xcex1-xcex, a milbemycin molecule or an avermectin molecule.
The compounds designated LL-F28249xcex1-xcex are (collectively) isolates from the fermentation broth of the microorganism Streptomyces cyaneogriseus subspecies noncyanogenus, deposited in the NRRL under deposit accession No. 15773. The method for preparation of the LL-F28249 compounds is disclosed in U.S. Pat. No. 5,106,994 and is incorporated herein by reference thereto.
The 23-oxo (keto) and 23-imino derivatives of LL-F28249xcex1-xcex compounds, useful in the pour-on formulations of this invention, are disclosed in U.S. Pat. No. 4,916,154, incorporated herein by reference thereto. Although U.S. Pat. No. 4,916,154 indicates that the 23-oxo (keto) and 23-imino derivatives of LL-F28249xcex1-xcex may be administered by pouring on the skin of an animal via a solution, it only suggests that the active compound may be dissolved in dimethylsulfoxide, propylene glycol or the like or in a combination of solvents. These formulations are not entirely satisfactory since the use of dimethylsulfoxide can cause instability of the 23-(oxo) or 23-imino derivatives of LL-F28249xcex1-xcex and/or leave a malodorous scent on the treated animal. The propylene glycol compositions tend to be sticky and collect dust and dirt and debris from the animals"" surroundings.
The pour-on veterinary compositions of this invention have the following formulations:
These compositions may be prepared by dissolving, dispersing or emulsifying about 0.1% to 5.0% w/v of the active ingredient, i.e. a compound selected from the group consisting of LL-F28249xcex1-xcex, a 23-oxo or 23-imino derivative of said compound LL-F28249xcex1-xcex, a milbemycin molecule or an avermectin molecule, in a mixture consisting essentially of 5.0% to 20.0% w/v of an aromatic solvent having a Kauri-butanol value between about 90 to about 96, a mixed aniline point between about 13.4xc2x0 C. to about 15.4xc2x0 C. and a specific gravity @ 15.6xc2x0/15.6xc2x0 C. of about 0.872 to about 0.985; about 1.0% to about 15.0% w/v of PPG-2 myristyl ether propionate; if present, about 1.0% w/v to about 15.0% w/v of a polybutene having a number average molecular weight range of 320 to 3000; and the remainder of the mixture a pharmacologically acceptable oil such as mineral or vegetable oil. Pour-on formulations prepared as described above with LL-F28249xcex1, LL-F28249xcex2, 23-(O-methyloxime)-LL-F28249xcex1 or 23-(O-methyloxime)-LL-F28249xcex2, are especially effective for controlling endo- and ectoparasites on mammalian quadrupeds.
The pour-on compositions of the invention may also be prepared by dissolving, dispersing or emulsifying about 0.1% to 5.0% w/v of a compound selected from the group consisting of LL-F28249xcex1-xcex, a 23-oxo or 23-imino derivative of said antibiotic LL-F28249xcex1-xcex, a milbemycin molecule and an avermectin molecule, in butoxyethoxyethanol. Pour-on formulations prepared as described above with LL-F28249xcex1, LL-F28249xcex2, 23-(O-methyloxime)-LL-F28249xcex1 or 23-(O-methyloxime)-LL-F28249xcex2, are especially effective for controlling endo- and ecto-parasites on mammalian quadrupeds. The admixture of up to about 15.0% w/v of polysorbate 80 with the above composition is optional.
Excipients such as dyes, antimicrobial agents, antioxidants or mixtures thereof may be included in the compositions of the invention. The amounts of said excipients suitable for use in the invention range from about 0.005% to 2.0% on a weight/volume basis.
Dyes suitable for use in the present invention include anthraquinone dyes, azo dyes and the like. Examples of antimicrobial agents useful in the compositions of the present invention are benzoic acid derivatives, methylparaben, propylparaben and the like. And antioxidants suitable for use in the compositions of the invention include butylated hydroxytoluene, butylated hydroxyanisoles, tertiarybutylhydroxyquinolone, sodium bisulfite, sodium metabisulfite, propyl gallate and the like and mixtures thereof.
Advantageously, the compositions of the present invention are well tolerated by the animals and non-damaging to the animals"" skin, hide or hair. The formulations are non-malodorous. They spread well and rapidly over the animal""s body and the active ingredient thereof is found to be readily absorbed through the hide or skin of the treated animals. A further benefit is that the compositions retain efficacy on wet skin or hide of the animal and resist wash off during precipitation such as rain. The term xe2x80x9cwater-fastxe2x80x9d used herein is intended to mean that the compositions resist being washed off in typical wet weather such as rainfall, snowfall, etc.
The preferred active ingredients useful in the preparation of the compositions of this invention have the following structures:
23-(O-methyloxime)-LL-F28249xcex1
and 
The compositions of this invention are highly effective for protecting or treating farm and companion animals, particularly mammalian quadrupeds such as cattle, sheep, deer, horses, swine, goats, dogs, cats and the like, against infection and infestation by helminths, nematodes, acarids and arthropod endo- and ectoparasitic insects.
Helminthiases is a widespread disease found in many farm and companion animals and responsible for significant economic losses throughout the world. Among the helminths most frequently encountered are the group of worms referred to as nematodes. The nematodes are found in the intestinal tract, heart, lungs, blood vessels and other body tissues of animals and are a primary cause of anemia, weight loss and malnutrition in the infected animals. They do serious damage to the walls of the gastrointestinal tract and the tissue of the organs in which they reside and, if left untreated, may result in death to the infected animals.
The nematodes most commonly found to be the infecting agents of animals include Haemonchus and Ostertagia generally found in the stomach; Cooperia, Oesphagostomum and Nematodirus generally found in the intestinal tract and Dictyocaulus found in the lungs. Treatment of animals to prevent infestation thereof by the above nematodes or to reduce or control the proliferation of these infecting agents in animals is thus an important and desirable advantage of the present invention.
Besides controlling helminths and nematodes, the present invention also controls several arthropod endo- parasitic infestations such as cattle grub infestations.
It has been further found that acarid and arthropod ectoparasitic insect infestations may be controlled, prevented or eliminated by applying to said animals an acaricidally or ectoparasiticidally effective amount of the above-described LL-F28249 compound or derivative thereof or milbemycin or avermectin molecule. This can be achieved by applying the active compound to the skin, hide and/or hair of the animals, usually in the form of a liquid formulated composition in sufficient amount to provide the treated animal with about 0.1 mg to 5.0 mg of active compound per kg of animal body weight. In practice it is found that generally 0.2 mg to 2.0 mg of LL-F28249xcex1, LL-F28249xcex2, 23-(O-methyloxime)-LL-F28249xcex1 or 23-(O-methyloxime)-LL-F28249xcex2, is sufficient to control helminths such as Ostertagia circumcincta, Haemonchus contortus and Trichostrongylus colubriformis. 
It has also been found that the pour-on composition disclosed in this application, which contains 23-(O-methyloxime)-LL-F28249xcex1 as the active ingredient, provides excellent control of the biting louse, Damalinia ovis and Damalinia bovis. Moreover, it has been found that this formulation which contains 23-(O-methyloxime)-LL-F28249xcex1 is unique in its ability to provide superior control of Psoroptes ovis which cause psoroptic mange on animals, such as cattle and sheep. This active ingredient also finds beneficial use in treating or controlling chorioptic, sarcoptic and demodectic mange on an animal which has been caused by infestation of Chorioptes bovis, Sarcoptes scabiei and the Demodex species, respectively.